APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons
Accumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer’s disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-st...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-05-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124715003599 |
| _version_ | 1811319510261563392 |
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| author | Steven Moore Lewis D.B. Evans Therese Andersson Erik Portelius James Smith Tatyana B. Dias Nathalie Saurat Amelia McGlade Peter Kirwan Kaj Blennow John Hardy Henrik Zetterberg Frederick J. Livesey |
| author_facet | Steven Moore Lewis D.B. Evans Therese Andersson Erik Portelius James Smith Tatyana B. Dias Nathalie Saurat Amelia McGlade Peter Kirwan Kaj Blennow John Hardy Henrik Zetterberg Frederick J. Livesey |
| author_sort | Steven Moore |
| collection | DOAJ |
| description | Accumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer’s disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Aβ peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by β-secretase and γ-secretase inhibition, as well as γ-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular Aβ signaling to neurons. |
| first_indexed | 2024-04-13T12:44:23Z |
| format | Article |
| id | doaj.art-1e9122a378f34938a203199646537dff |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-13T12:44:23Z |
| publishDate | 2015-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-1e9122a378f34938a203199646537dff2022-12-22T02:46:25ZengElsevierCell Reports2211-12472015-05-0111568969610.1016/j.celrep.2015.03.068APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex NeuronsSteven Moore0Lewis D.B. Evans1Therese Andersson2Erik Portelius3James Smith4Tatyana B. Dias5Nathalie Saurat6Amelia McGlade7Peter Kirwan8Kaj Blennow9John Hardy10Henrik Zetterberg11Frederick J. Livesey12The Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UKThe Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UKDepartment of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 91 Stockholm, SwedenDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 80 Molndal, SwedenThe Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UKThe Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UKThe Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UKThe Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UKThe Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UKDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 80 Molndal, SwedenDepartment of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 1PJ, UKDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 80 Molndal, SwedenThe Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UKAccumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer’s disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Aβ peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by β-secretase and γ-secretase inhibition, as well as γ-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular Aβ signaling to neurons.http://www.sciencedirect.com/science/article/pii/S2211124715003599 |
| spellingShingle | Steven Moore Lewis D.B. Evans Therese Andersson Erik Portelius James Smith Tatyana B. Dias Nathalie Saurat Amelia McGlade Peter Kirwan Kaj Blennow John Hardy Henrik Zetterberg Frederick J. Livesey APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons Cell Reports |
| title | APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons |
| title_full | APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons |
| title_fullStr | APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons |
| title_full_unstemmed | APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons |
| title_short | APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons |
| title_sort | app metabolism regulates tau proteostasis in human cerebral cortex neurons |
| url | http://www.sciencedirect.com/science/article/pii/S2211124715003599 |
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